The antioxidant, butylated hydroxyanisole (BHA), has been widely used to stabilize fatty foods. Dietary BHA was found to inhibit chemically induced neoplasia in a number of tissues of laboratory animals. Recently, it was found that at high concentrations dietary BHA induced papillomas and squamous cell carcinoma in the forestomach of hamster and rat respectively. The overall objective of this proposed research is to elucidate the mechanism of carcinogenic action of BHA in the forestomach of male Syrian golden hamster. Commercial BHA contains two isomers of BHA and five minor contaminants. We propose to determine the carcinogenicity of the pure BHA isomers and that of the five phenolic contaminants. The synergistic effect of the BHA isomers will be studied. Catechols and their corresponding semi-o-quinones and/or o-quinones have been postulated as the proximate and ultimate carcinogenic species of carcinogenic phenols respectively. Since BHA is a phenol that can be metabolized to catechols which may be carcinogenic in the forestomach of the hamster the catechols and the corresponding o-quinones of BHA will be synthesized and their carcinogenicity determined. While BHA was carcinogenic to the forestomach of hamster and rat it was not carcinogenic to B6C3F1 mice. To determine the importance of species difference the carcinogenicity of the activated metabolites of BHA will be studied in the forestomach of the mouse. If catechol formation is an essential step in the activation of BHA isomers then any substituent that can block the formation of these metabolites will be able to block the carcinogenicity of BHA as well. To eliminate the carcinogenicity of BHA fluorine atoms will be introduced ortho to the phenolic function of the BHA molecules such that catechol formation will be blocked by the presence of the halogen atom. The carcinogenicity of these fluorinated compounds will be studied. Enzyme systems that are responsible for the activation and detoxification of carcinogens may be affected by different concentrations of BHA. The effect of high BHA concentration on these enzymes will be assayed in the forestomach of hamster and mice. P[henols are ubiquitous compounds in the environment. By determining the mechanism of action of BHA we hope to understand the possible health hazard of other phenolic antioxidants and naturally occurring phenols. Since BHA and related compounds are inhibitors of chemical carcinogenesis a thorough understanding of its mechanism may assist us in designing antioxidants that have high inhibitory activity without the carcinogenic effect.